Cardiovascular disease (CVD) and depression are two complex diseases that often co-occur. However, the potential mechanisms linking depression and CVD remain unclear. Recent studies suggest that common genetic vulnerability may explain the comorbidity of these two disorders. Because studies in human and animal models have consistently reported the role of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in the risk of both depression and CVD, genetic abnormalities in the HPA system may thus represent an important pathophysiological mechanism that contributes to the co-occurrence of depression and CVD. The overall objective of this project is to test the hypothesis that genetic variants within the HPA-related pathways are key determinants for the vulnerability to both depression and CVD. We will genotype 19 key candidate genes involved in the HPA axis and related pathways using a twin sample including 640 middle-aged male twins from the Vietnam Era Twin Registry (VETR). All these twins were extensively phenotyped in recent studies, including information on depressive symptoms, subclinical CVD, detailed measurements of stress and other psychological variables, as well as behavioral and social-demographic variables. The proposed study using twins provides a unique opportunity to tease out gene-environment effects that are usually confounded by other factors in classical genetic studies. Findings from this study may not only open new windows into the mechanisms underlying these two common disorders but in the future may also provide guidance for optimal therapeutic treatments particularly for genetically susceptible individuals. PUBLIC HEALTH RELEVANCE: This study proposes to identify common genetic polymorphisms in the HPA axis and related biological pathways for the comorbidity of depression and cardiovascular disease using a well-phenotyped twin database from the Vietnam Era Twin Registry. Results will provide valuable data for deciphering the genetic basis of cardiovascular and psychiatric diseases.